Abstract
BackgroundAsians have the highest incidence of gastric cancer (GC), and the prognosis of Asian GC is poor. Furthermore, the therapeutics for Asian GC is limited because of genetic heterogeneity and screening difficulty at the early stage. This study aimed to develop an immune-related gene (IRG)-based prognostic signature and to explore prognosis-related regulatory mechanism and therapeutic target for Asian GC.MethodsTo elucidate the prognostic value of IRGs in Asian GC, a comprehensive analysis of IRG expression profiles and overall survival times in 364 Asian GC patients from the Asian Cancer Research Group (ACRG) and The Cancer Genome Atlas (TCGA) databases was performed, and a novel prognostic index was established. To further explore regulatory prognosis mechanisms and therapeutic targets, a tumor immunogenomic landscape analysis, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was performed.ResultOur analysis allowed the creation of an optimal risk assessment model, the Asian-specific IRG-based prognostic index (ASIRGPI), which showed a high accuracy in predicting survival in Asian GC. We also developed an ASIRGPI-based nomogram to predict the 3- and 5-year overall survival (OS) of Asian GC patients. The impact of the ASIRGPI on the worse prognosis of Asian GC was possibly related to the stromal component remodeling. Specifically, TGFβ gene sets were significantly associated with the ASIRGPI and worse prognosis. Immunomodulatory gene analysis further revealed that TGFβ1 and EDNRB may be the novel potential therapeutic targets for Asian GC.ConclusionsAs a tumor microenvironment-relevant gene set-based prognostic signature, the ASIRGPI model provides an effective approach for evaluating the prognosis of Asian GC and may even prolong OS by enabling the selection of individualized therapy with the novel targets.
Highlights
Gastric cancer (GC) was the fourth most common malignant tumor and the third leading cause of cancer mortality in 2019 according to global cancer statistics [1, 2]
Gene set enrichment analysis (GSEA) revealed that TGFb signaling, coagulation, myogenesis, TNFA signaling, and epithelial– mesenchymal transition (EMT) were enriched in the TCGASTAD white cohort, while MYC targets V2, DNA repair, G2M checkpoint, MYC targets V1, and E2F targets were enriched in the The Cancer Genome Atlas database (TCGA)-stomach adenocarcinoma (STAD) Asian cohort (Figure 2B and Supplementary Figure S2)
After excluding patients with an overall survival (OS) of
Summary
Gastric cancer (GC) was the fourth most common malignant tumor and the third leading cause of cancer mortality in 2019 according to global cancer statistics [1, 2]. Previous research [5–7] reported that the prognosis of AGC is better as it is often diagnosed at earlier tumor stages, at a more distal anatomic site, and at a younger age and receives more aggressive treatment. Considering that the prognosis of GCs depends on tumor stage and on heterogeneous and epigenetic molecular features [8, 9], the differences in GC survival patterns and the possible causes of survival disparities among different ethnic groups have not yet been clarified. Asians have the highest incidence of gastric cancer (GC), and the prognosis of Asian GC is poor. The therapeutics for Asian GC is limited because of genetic heterogeneity and screening difficulty at the early stage. This study aimed to develop an immune-related gene (IRG)-based prognostic signature and to explore prognosis-related regulatory mechanism and therapeutic target for Asian GC
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